A Critical Review of Validation, Blind Testing, and Real-World Use of Alchemical Protein-Ligand Binding Free Energy Calculations.

A Critical Review of Validation, Blind Testing, and Real-World Use of Alchemical Protein-Ligand Binding Free Energy Calculations.

Curr Top Med Chem. 2017 Apr 14;:

Authors: Abel R, Wang L, Mobley DL, Friesner RA

Abstract
Protein-ligand binding is among the most fundamental phenomena underlying all molecular biology, and a greater ability to more accurately and robustly predict the binding free energy of a small molecule ligand for its cognate protein is expected to have vast consequences for improving the efficiency of pharmaceutical drug discovery. We here briefly review a number of scientific and technical advances that have enabled alchemical free energy calculations to recently emerge as a preferred approach, and critically consider proper validation and effective use of these techniques. In particular, we characterize a selection bias affect which may be important in prospective free energy calculations, and introduce a strategy to improve the accuracy of the free energy predictions should they arise.

PMID: 28413950 [PubMed - as supplied by publisher]

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